GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation

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Abstract
GATA-binding protein 3 (GATA3) is a zinc-finger transcription factor that is continually expressed in a highly regulated manner throughout T-cell development and CD4+ T helper (TH)-cell differentiation. At the earliest stages of T-cell development, GATA3 is required for commitment to the T-cell lineage. However, forced expression of GATA3 in pre-committed double negative 1 (DN1) or DN2 thymocytes is toxic, and in developing B cells it diverts the development of cells to the mast-cell lineage. So, the expression levels of GATA3 must be 'just right' for successful commitment to the T-cell lineage. After T-cell-lineage commitment, GATA3 has a role in β-selection, such that mice lacking GATA3 at the DN3 stage of development exhibit partial arrest at the DN3 stage and impairment of T-cell receptor β-chain (TCRβ) protein expression. The nature and extent of this function of GATA3 are still unclear owing to the current limitations of T-cell-specific conditional knockout technology. Two transcription factors, GATA3 and T-helper-inducing POZ/Kruppel-like factor (ThPOK; encoded by Zbtb7b, which was recently found to be mutated in the helper-deficient spontaneous mutant mouse strain), are both crucial for CD4 single positive (SP) thymocyte development. The development of MHC class II-restricted thymocytes that lack or express a mutant form of ThPOK is diverted to the CD8 lineage, indicating that ThPOK functions in CD4- or CD8- lineage determination. By contrast, GATA3-deficient thymocytes that develop in a MHC class II-restricted environment give rise to no or few CD8-lineage cells. Delineating the distinct functions of these two factors is further complicated by evidence showing that GATA3 upregulates ThPOK expression but restoration of ThPOK expression in GATA3-deficient mice fails to restore CD4 SP thymocyte development. GATA3 is both necessary and sufficient for the development of TH2 cells, largely because interleukin-4 receptor (IL-4R) signalling through signal transducer and activator of transcription 6 (STAT6) induces GATA3 expression in a positive-feedback loop. STAT6-independent TH2-cell differentiation signals, such as triggering of the TCR, activation of IL-2R–STAT5A signalling and engagement of Notch receptors, also depend on GATA3 to promote IL-4 production. Control of the production of individual TH2-type cytokines by GATA3 is accomplished by distinct mechanisms, as shown by structure–function analyses.